Dementia is a condition of deteriorating mentality that is characterized by marked decline in the individual's former intellectual level, including memory loss, impaired judgment, speech and orientation, and is often accompanied by emotional apathy. (WEBSTER'S MEDICAL DESK DICTIONARY, Merriam-Webster, Inc., Springfield, Mass. p.169 (1986)).
A leading cause of dementia is Alzheimer's disease,(AD), a neurodegenerative disorder affecting 17 to 20 million people worldwide (Yamazaki, T., et al., J. Cell. Biol., 129;431-442 (1995); Brinaga, M., Science, 269:917-918 (1995); Lavy-Lahad, E., et al., Science, 269:970-972 (1995); Lavy-Lahad, E., et al., Science, 269:973-977 (1995)). AD is characterized by progressive dementia together with neuropathological findings of "isenile plaques" in the brain formed by deposits of .beta.-amyloid protein, surrounded by clusters of degenerating neurons. .beta.-amyloid protein itself is a fragment of the 770 amino acid membrane bound .beta.-amyloid precursor protein (.beta.APP) that is expressed in both neuronal and non-neuronal tissues.
Muteins of .beta.APP have been produced for the purpose of developing a .beta.APP substrate system wherein .beta.APP is cleavable or not cleavable such that .beta.AP producing enzymes and inhibitors thereof may be isolated.
The specific cause of Alzheimer's disease has not yet been determined. A mutation in the .beta.APP gene in families with one form of autosomal dominant AD was found to be associated with increased .beta.-amyloid synthesis and aggregation in the brain. A receptor for .beta.APP has been identified as the low density lipoprotein receptor-related protein, ApoE, and it has been postulated that this receptor protein, the enzyme responsible for .beta.APP cleavage in the cell membrane, production of .beta.APP and/or production of extracellular matrix molecules may be abnormal individually or in combination in AD patients, resulting in excess .beta.-amyloid deposition and the observed neurotoxicity. However, the mechanism by which other known .beta.APP gene mutations cause AD, as well as the pathophysiology of non-familial AD in which .beta.APP gene mutations have not been recognized, is not understood.
Therefore, diagnosing Alzheimer's disease as the cause of an individual's dementia, as well as treating AD and developing drug therapies is very difficult. Although recent reports of using Positron-emission tomography (PET) (Reiman, E. M., et al., New Eng. J. Med., 334:752-758 (1996), determining the genotype of an individual's ApoE, or measuring the levels of .beta.-amyloid protein in cerebral spinal fluid may be promising, diagnosis of Alzheimer's is currently confirmed only upon autopsy to determine the presence of .beta.-amyloid senile plaques.
In vitro systems employed to study Alzheimer's disease to date consist of malignant, or transformed cells that are not of neural crest origin, or lower vertebrate neuronal cultures. It would be of great advantage to have an Alzheimer's disease model system using normal human neural crest-derived cells. However, to date, no such model system has been developed.
Moreover, recent studies have shown that damage to CNS neurons due to Alzheimer's disease begins years before clinical symptoms are evident. (Reiman, E. M., et al., New Eng. J. Med., 334:752-758 (1996)), suggesting that therapy could begin in the pre-symptomatic phase of the disease if a sensitive diagnostic test and targeted therapies were available. There exists a great need to determine the physiological mechanisms involyed with the disease and for an accurate and easy to perform assay to evaluate the risk of developing Alzheimer's disease.